DESCRIPTION: The focus of this application is HSV-encoded immediate-early transactivator IE110 (ICP0) and its interaction with other immediate-early and cellular regulatory proteins. The IE110 protein targets to novel intranuclear punctate domains or PML oncogenic domains (PODs) where it displaces two cellular growth suppressor proteins, including the proto-oncogene PML. Both IE110 and PML have a novel non-DNA binding zinc finger domain known as the RING finger which is critical for their proper function. The overall goals of this proposal are to define the functional consequences of IE110 and POD protein:protein interactions and to understand how they contribute to the HSV gene regulation cascade and virus reactivation. Novel mutant viruses and inducible cell lines will be generated as well as improved assays investigating the role of IE110 in bypassing growth arrest blocks in quiescent (G0) cells and in reactivating virus from model cell culture systems. Emphasis will be placed on functional interactions between IE110, PML and SP100 and on identifying cellular proteins that may bind to the RING finger domain and mediate its functions.